Fatty acids are essential for life. Besides storing energy, these fats are part of our makeup; they are formed in our healthy cells, muscles, nerves, and organs. The omega-3 polyunsaturated fatty acids are found in marine oils and are well known for their benefit as orally administered supplements for the maintenance of healthy arteries. A multitude of research has underscored the major role of essential fatty acids play as a defense against disease and age-related disorders. Gamma-linolenic acid (GHA) and docosahexaenoic acid (DHA) have been shown to protect against age related disorders such as heart disease, hypertension, elevated cholesterol, insulin resistance, dementia, memory loss, and atherosclerosis that can lead to heart disease, stroke, and elevated cholesterol levels. In youth, the fatty acids GLA, DHA, and eicosapentaenoic acid (EPA) are produced through metabolic processes involving the enzyme delta-6 desaturase. Unfortunately, this enzyme diminishes with age, leading to a deficiency of essential fatty acids that are needed to respond optimally to trauma.
In general, the “good” fats are unsaturated fats from oils of vegetables, nuts, and some fish. “Bad” fats are saturated fats, typically from animal fats, dairy products, etc. Without adequate levels of good fats, dangerous saturated fats will replace the essential fatty acids in our cells, reducing membrane fluidity and efficiency, starting the process of premature aging, and lessening the ability of the body to appropriately respond to trauma. Supplementation with the right proportions of fatty acids can maximize the production of anti-inflammatory prostaglandins (E1 and E3), while suppressing pro-inflammatory prostaglandin E2.
In addition, omega-3 fatty acids have been used as emulsion vehicles for the oral administration of poorly water-soluble therapeutic agents, as taught in U.S. Pat. No. 6,284,268, to Mishra. Their derivatives have been used to prevent a psychiatric, neurological or other central or peripheral nervous system disease, according to Horrobin, U.S. Pat. No. 6,479,544, who teaches a composition comprising EPA in combination with arachidonic acid or an arachidonic acid precursor such as dihomo-gammalinolenic (DGLA) or GLA. U.S. Pat. No. 6,361,806, to Allen, teaches the topical application of the linoleic acids, including gamma-linoleic acid, to the skin to effect changes in subcutaneous adipose tissue, and methods for ameliorating diseases of the subcutaneous tissue, primarily fibrocystic disease of the breast.
The variety of substances used to sooth irritated skin is limited only by the imagination of the formulator. Natural oils, such as aloe vera, are used extensively and several U.S. Patents are issued for specific formulas such as U.S. Pat. No. 6,193,987, to Harbeck, which teaches a lubricating composition for hands and skin comprised of organic safflower oil, flaxseed oil, tincture of benzoin, and organic beeswax blended in a cream-like base. U.S. Pat. No. 5,244,679, to Freston, teaches the alleviation of minor human skin irritations with topical application of glycerin, stearic acid, cocoa butter and boric acid blended together in a creamy base.
The omega-3 polyunsaturated fatty acids have also been sought as topical preparations, but technology in the field has had poor success in topical pharmaceutical formulations of fish oil-derived DHA and EPA. One of the main technical obstacles that has heretofore prevented their effective topical use is their very unpleasant smell, generated after application, and caused by oxidization of marine lipids from atmospheric oxygen and/or cutaneous enzymes.
The “off” or “rancid” odor associated with these oils is produced, in part, by oxidation of polyunsaturated fatty acids. Since highly unsaturated fatty acids occur in greater proportion in marine oils than in land animal- and vegetable-derived oils, rancidity is a greater problem when using marine sources. Oxidation of polyunsaturated fatty acids leads to the formation of hydroperoxides. The decomposition products of these hydroperoxides, such as aldehydes resulting from oxidation of marine animal oils, exhibit the unpleasant odors characteristic of rancid oils. Certain decomposition intermediates may also contribute to the problem.
Hence, the use of creams, lotions or gels containing omega-3 polyunsaturated fatty acids, which are initially odorless or pleasantly perfumed, is limited by their very unpleasant and repellent smell after application, which emanate from application sites and adhere to clothes that come into contact with them. As a result, consumer acceptability of topical compositions is low.
These odors appear to be characteristic of the fatty acids or long-chain hydrocarbons associated with natural oil compositions. In fish oils, for example, the “fishy” odor is postulated to be the result of interaction during oxidation between nitrogenous moieties and unsaturated glycerides present in the oil composition. Another theory regarding the source of the odor is that the unsaponifiable fraction (i.e., 5-hydrocarbon, sterol, methyl-sterol, long-chain alcohol, triterpene alcohol, pigment, trace materials and the like) of the oil composition is the component with which the “fishy” odor is associated.
In any event, this odor is not permanently removable even by drastic steam deodorization procedures (i.e., prolonged vacuum treatment at elevated temperatures, such as from about 230 degree to 260 degree. C.). The odor returns upon exposure of the “deodorized” oil to oxygen.
Since marine oils are capable of imparting advantageous properties to topical compositions, efforts have been made to overcome the aroma problem. These efforts were complicated by the fact that many processes alter the composition of fats and fatty acids. Exemplary processing techniques are refining, high temperature clay bleaching, high temperature-high pressure fat splitting, transesterification reactions and partial hydrogenation. Alterations arising from processing include cis-trans isomerization, conjugation of polyunsaturates, polymerization, dehydrogenation and the like.
Several strategies have emerged for using malodorous oils in topical compositions. In the first, only amounts of oil small enough not to adversely impact the odor of the complete topical composition were used. This strategy is not effective when higher concentrations of oil are required or desirable. The use of perfumes or any other deodorizing agent, even if intense and strong, is useless. In fact, upon application of the cream or of any other topical form to the skin, the perfume volatile components evaporate faster than the higher boiling esters of polyunsaturated fatty acids, which assume, in a very short time, a very unpleasant smell.
U.S. Pat. No. 5,472,705, to Bruzzese, teaches the addition of phenolic antioxidants to topical compositions of the esters of omega-3 polyunsaturated fatty acids to hinder the decomposition and the generation of very unpleasant and repellent smells. Horrobin, in U.S. Pat. No. 6,479,544, provides an example for topical use of EPA with GLA, but neither addresses the problem of odor in a topical composition, discloses the addition of DHA or lavender oil to the EPA-GLA composition, nor teaches the need to use molecularly distilled fish oils in the specific proportions with GLA that are appropriate for topical administration.
U.S. Pat. No. 5,650,157, to Bockow, teaches a method to prepare stable, deodorized oils by adding an amount of a deodorizing agent effective to substantially reduce the odor of the derived oil composition, fraction or combination thereof. Bockow teaches a multi-step process for the deodorization of marine oils wherein warm water is added to ground raw marine product, the pH is adjusted by the addition of acid to between 2.0 and 3.5, preferably about 2.8, the solution is mixed gently and allowed to stand at room temperature for approximately 24 hours to allow the oil to separate. Following this, the solution is mixed and allowed to stand again two or three times, requiring several days for the preparation of the deodorized oils. After the oil is drawn off, particles are removed, and the oil is filtered, heated, and allowed to cool gradually.
U.S. Pat. No. 6,551,602, to Barrett teaches a conjugated linoleic acid composition containing a phenolic compound selected from the group consisting of epigallocatechin gallate, genistein, green tea extract and soy extract as a treatment for wrinkles.
Unexpectedly, this inventor has discovered that the use of molecularly distilled fish oils to supply EPA and DHA diminishes the generation of unpleasant smells and the need for phenolic antioxidants as taught by Bruzzese. The molecularly distilled fish oils, in a specific proportion of fish oils with GLA, mixed tocopherols, and lavender oil, were found to have remarkable success in treating traumatic conditions of the skin.
Radiation Dermatitis
Radiation therapy has traditionally been the treatment of choice for locally or regionally advanced cancer, but its therapeutic efficacy is often hindered by limited tolerance of normal tissues and by tumor radio resistance. To improve therapeutic outcome, radiotherapy is frequently combined with chemotherapeutic drugs that are themselves cytotoxic and may sensitize cells to radiation. Milas L, et al, 17 (5 Suppl 5) ONCOLOGY (Hunting) 15-24 (2003). Radiation may cause severe burns of the skin and surrounding tissue as well as permanent changes in pigmentation. As many as 95% of patients treated with radiation therapy for cancer will experience a skin reaction. Porock D, Nikoletti S, Kristjanson L 19(4) PLAST SURG NURS. 185-92 (1999).
Some patients suffer radiation-induced skin injuries and younger patients may face an increased risk of future cancer. Davis MM, et al 20(4) J AM ACAD DERMATOL 608-16 (1989). Interventionists are suffering injury and are exposing their staff to high doses of radiation. In some interventional procedures, skin doses to staff approach those experienced in some cancer radiotherapy fractions. Radiation-induced skin injuries occur in patients due to the use of inappropriate equipment and, more often, poor operational technique. Valentin, 30(2) J. ANN ICRP, 7-67 (2000). Others report that such burns, when experienced in the hand, require aggressive debridement and immediate coverage with well-vascularized flaps, either regional or free-tissue transfers to achieve adequate wound healing and the most rapid, effective return of function with rapid institution of therapeutic modalities. Milanov NO, Shilov BL, Tjulenev AV 92(2) PLAST RECONSTR SURG. 294-300(1993).
Aloe vera has been tried without improvement in the results of irradiated breast tissue, Heggie S, et al, 25(6) CANCER NURS. 442-51 (2002), as has topical Vitamin C, Halperin EC, et al, 26(3) INT J RADIAT ONCOL. BIOL. PHYS 413-6 (1993). Other groups report that prophylactic and ongoing use of topical therapy with either topical corticosteroid or a dexpanthenol-containing emollient ameliorates, but does not prevent, radiation dermatitis. Schmuth, M, et al 146(6) BR J DERMATOL. 983-91(2002). Similarly, the increased effectiveness produced by the addition of a potent topical corticosteroid to an emollient cream is statistically significant as compared to the emollient cream itself in reducing acute radiation dermatitis but had no effect on pigmentation changes. Bostrom, A, et al, 59(3) RADIOTHER ONCOL. 257-65 (2001). Authors report that moist skin care with 3% urea lotion delays the occurrence and reduces the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors. Momm, F, et al, 179(10) STRAHLENTHER ONKOL. 708-12 (2003).
Biafine and Lipiderm had no radioprotective effect, Fenig E, 8(2) ONCOL. REP 305-9 (2001), while another group reported a significant dermato-cytoprotective effect of amifostine in its retrospective analysis. Kouvaris, J, 12(5) EUR J DERMATOL. 458-62 (2002).
Misoprostol, a prostaglandin E(1) analog, has been found to be an effective radioprotector in animal studies. It was shown to prevent to oncogenic transformation of Syrian hamster embryos exposed to radiation in utero. LaNasa P, 29(2) INT J RADIAT ONCOL. BIOL. PHYS. 273-5 (1994). However, results in humans were disappointing. Oral complications of radiation therapy seriously impact quality of life because of changes in taste, saliva, mucous, and eating. Johnson D J, et al, 54(5) INT J RADIAT ONCOL. BIOL. PHYS 1455-9 (2002). Oral administration of misoprostol produced inconsistent results in the prevention of oral mucositis in head and neck cancer patients treated with radiation. Hanson W R, et al 2(11) AM J THER. 850-857 (1995).
Recent advances in molecular biology have discovered many cellular molecules, including the cyclooxygenase-2 (COX-2) enzyme, which promote tumor cell survival and are responsible for tumor resistance to cytotoxic agents, that are being studied as potential targets for augmentation of response to radiation or chemotherapy. Milas L, et al, 17 (5 Suppl 5) ONCOLOGY (Hunting) 15-24 (2003)
None of the attempted treatments is completely successful and there is no “gold standard” in the prophylaxis and treatment of radiation dermatitis, creating a long-felt need to treat the dermatologic effects of radiation.
Burns
Usually the result of trauma, but occasionally due to self mutilation, burns are amongst the most serious conditions seen by medical personnel. Treatment is supportive, with antibiotics and fluid replacement followed by multiple skin grafting to restore the appearance as best as can be accomplished. The hypermetabolic response, which is mediated by hugely increased levels of circulating catecholamines, prostaglandins, glucagon and cortisol, causes profound skeletal muscle catabolism, immune deficiency, peripheral lipolysis, reduced bone mineralization, reduced linear growth, and increased energy expenditure. Murphy K D, Lee J O, and Herndon D N, 4(3) EXPERT OPIN PHARMACOTHER. 369-84 (2003). Burn-related immune disturbances, specifically the burn-related suppression of mesenteric lymph node T-cell proliferation and interleukin-2 production, were studied in rats and prevented when the rats were fed on a high-protein diet rich in glutamine, arginine, fish oil, and nucleotides. Choudhry, M A, 31(6) CRIT CARE MED 1764-70 (2003)
Topical treatments for the traumatic conditions produced by burns has not been remarkable. Jandera, et al, 26(3) BURNS 265-70 (2000) reported more rapid healing in both the Melaleuca alternifolia Hydrogel and water-cooled burns compared with the untreated controls. Tea tree oil, a known antiseptic, was ineffective in inhibiting bacterial growth in burns and therefore not recommended after clinical trial. Faoagali J, George N, Leditschke J F. 23(4) BURNS 349-51 (1997).
Sunburn
Sunburn is produced by the ultraviolet (UV) radiation of the sun and is mediated by inflammatory substance cyclooxygenase-2 and prostaglandins. Cyclooxygenase-2 expression is induced by ultraviolet irradiation; data suggest that tyrosine kinases and reactive oxygen intermediates are involved in this induction. Isoherranen, K, et al, 140(6) BR J DERMATOL 1017-22 (1999). The effects of ultra-violet radiation of the sun can be mitigated by oral supplementation with dietary fish oils. Following 3 months of fish oil, prostaglandin E2 decreased in both control and irradiated skin. Reduction of UV-induced trauma by fish oil may be due, at least partially, to lowered prostaglandin E2 levels. The photoprotection against UVA-provocation of a papular response suggests a clinical application for fish oil in polymorphic light eruption. Rhodes, L E, et al 105(4) J INVEST DERMATOL 532-5 (1995).
Exposure-Induced Wrinkles
Numerous measures have been attempted to retard the natural aging process of the human skin, which is greatly exacerbated by trauma, e.g. sunburn and windburn. The fashionable treatment of the day is the injection of Botulinum toxin to weaken the smooth muscle around the wrinkle and cause it to collapse, popularized as “Botox.” Redaelli, A, Forte, R, 5(3-4) J COSMET LASER THER 220-2 (2003). But other aggressive therapies are readily available, limited only by the courage of the recipient. Pyruvic acid peels, Ghersetich, I, 30(1) DERMATOL SURG 32-6 (2004), injectable collagen, Galadari H, Lebwohl M, 49(5 Suppl) J AM ACAD DERMATOL. S265-6 (2003), and laser skin resurfacing, Batra R S, 139(10) ARCH DERMATOL 1295-9 (2003), have all been used with mixed success and obvious risks.
There is a suggestion that gentler methodology may be as effective as injections and chemical peels. French researchers reported some success in the use of a preparation containing a fucose-rich polysaccharide as an active principle on the microdepressionary skin surface. In 17 out of 20 female volunteers, aged from 39 to 71 years, exhibited significant improvement of the skin surface relief after 4 weeks of treatment, as shown by the displacement of geometrical characteristics, towards a “younger” pattern, corresponding to a decrease of apparent age by 10-15 years. Robert C, Robert A, and Robert L, 51(10) PATHOL BIOL(PARIS) 586-90 (2003). Alpha-Lipoic Acid has also been demonstrated to have some effect, Beinter, H, 149(4) BR J DERMATOL 841-9 (2003), and is now found in a multitude of preparations available at any local pharmacy or supermarket.
Dermatomyfibroma
Dermatomyofibroma is a recently described, rare, benign proliferation of myofibroblasts of the skin, often as a reaction to minor trauma such as scratches and insect bites, mainly found in young women. Only a few cases have been reported in males, but a case was reported in a four year old boy. Rose C, Brocker E B, 16(6) PEDIATR DERMATOL 456-9 (1999). Treatment is generally by conservative excision; follow-up information revealed no evidence of recurrence. Kamino, H, 19(2) J CUTAN PATHOL 85-93 (1992). Occasionally, lesions can be resolved through prompt and frequent topical application of steroid cream or diphenhydramine.